Heteroaromatic and aromatic piperazinyl azetidinyl amides as monoacylglycerol lipase inhibitors

ABSTRACT

Disclosed are compounds, compositions and methods for treating diseases, syndromes, conditions and disorders that are affected by the inhibition of MGL, including pain. Such compounds are represented by Formula (I) as follows: 
     
       
         
         
             
             
         
       
         
         
           
             wherein R 1 , W and 
           
         
       
    
     
       
         
         
             
             
         
       
     
     are defined herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/171,661, filed on Apr. 22, 2009, which is incorporated by referenceherein in its entirety.

This application is related to provisional application entitled,Heteroaromatic and Aromatic piperazinyl Azetidinyl Amides asMonoacylglycerol Lipase Inhibitors, filed on Apr. 22, 2009, U.S.provisional patent application Ser. No. 61/171,660.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

The research and development of the invention described below was notfederally sponsored.

FIELD OF THE INVENTION

The present invention is directed to the use of a compound of formula(I) as herein defined for the treatment, amelioration and/or preventionof an MGL disorder in a subject, including a mammal and/or human, inwhich the disease, syndrome, or condition is affected by MGL.

BACKGROUND OF THE INVENTION

Cannabis sativa has been used for the treatment of pain for many years.Δ⁹-tetrahydrocannabinol is a major active ingredient from Cannabissativa and an agonist of cannabinoid receptors (Pertwee, Brit JPharmacol, 2008, 153, 199-215). Two cannabinoid G protein-coupledreceptors have been cloned, cannabinoid receptor type 1 (CB₁, Matsuda etal., Nature, 1990, 346, 561-4) and cannabinoid receptor type 2 (CB₂,Munro et al., Nature, 1993, 365, 61-5). CB₁ is expressed centrally inbrain areas, such as the hypothalamus and nucleus accumbens, as well asperipherally in the liver, gastrointestinal tract, pancreas, adiposetissue and skeletal muscle (Di Marzo et al., Curr Opin Lipidol, 2007,18, 129-140). CB₂ is predominantly expressed in immune cells, such asmonocytes (Pacher et al., Amer J Physiol, 2008, 294, H1133-H1134), and,under certain conditions, also in the brain (Benito et al., Brit JPharmacol, 2008, 153, 277-285) and in skeletal (Cavuoto et al., BiochemBiophys Res Commun, 2007, 364, 105-110) and cardiac (Hajrasouliha etal., Eur J Pharmacol, 2008, 579, 246-252) muscle. An abundance ofpharmacological, anatomical and electrophysiological data, usingsynthetic agonists, indicate that increased cannabinoid signalingthrough CB₁/CB₂ promotes analgesia in tests of acute nociception andsuppresses hyperalgesia and/or allodynia in models of chronicneuropathic and inflammatory pain (Cravatt et al., J Neurobiol, 2004,61, 149-60; Guindon et al., Brit J Pharmacol, 2008, 153, 319-334).

Efficacy of synthetic cannabanoid receptor agonists is well documented.Moreover, studies using cannabinoid receptor antagonists and knockoutmice have also implicated the endocannabinoid system as an importantmodulator of nociception. Anandamide (AEA) (Devane et al., Science,1992, 258, 1946-9) and 2-arachidinoylglycerol (2-AG) (Mechoulam et al.,Biochem Pharmacol, 1995, 50, 83-90; Sugiura et al., Biochem Biophys ResCommun, 1995, 215, 89-97) are two major endocannabinoids. AEA ishydrolyzed by fatty acid amide hydrolase (FAAH) and 2-AG is hydrolyzedby monoacylglycerol lipase (MGL) (Piomelli, Nat Rev Neurosci, 2003, 4,873-884). Genetic ablation of FAAH elevates endogenous AEA and resultsin a CB₁-dependent analgesia in models of acute and inflammatory pain(Lichtman et al., Pain, 2004, 109, 319-27), suggesting that theendocannabinoid system functions naturally to inhibit nociception(Cravatt et al., J Neurobiol, 2004, 61, 149-60). Unlike the constitutiveincrease in endocannabinoid levels using FAAH knockout mice, use ofspecific FAAH inhibitors transiently elevates AEA levels and results inantinociception in vivo (Kathuria et al., Nat Med, 2003, 9, 76-81).Further evidence for an endocannabinoid-mediated antinociceptive tone isdemonstrated by the formation of AEA in the periaqueductal gray, a knownpain center, following noxious stimulation in the periphery (Walker etal., Proc Natl Acad Sci USA, 1999, 96, 12198-203) and, conversely, bythe induction of hyperalgesia following the administration of CB₁antisense RNA in the spinal cord (Dogrul et al., Pain, 2002, 100,203-9).

With respect to 2-AG, intravenous delivery produces analgesia in thetail flick (Mechoulam et al., Biochem Pharmacol, 1995, 50, 83-90) andhot plate (Lichtman et al., J Pharmacol Exp Ther, 2002, 302, 73-9)assays. In contrast, it was demonstrated that 2-AG given alone is notanalgesic in the hot plate assay, but when combined with other2-monoacylglycerols (i.e., 2-linoleoyl glycerol and 2-palmitoylglycerol), significant analgesia is attained, a phenomenon known as the“entourage effect” (Ben-Shabat et al., Eur J Pharmacol, 1998, 353,23-31). These “entourage” 2-monoacylglycerols are endogenous lipids thatare co-released with 2-AG and potentiate endocannabinoid signaling, inpart, by inhibiting 2-AG breakdown, most likely by competition for theactive site on MGL. This suggests that synthetic MGL inhibitors willhave a similar effect. Indeed, URB602, a relatively weak synthetic MGLinhibitor, showed an antinociceptive effect in a murine model of acuteinflammation (Comelli et al., Brit J Pharmacol, 2007, 152, 787-794).

Although the use of synthetic cannabinoid agonists have conclusivelydemonstrated that increased cannabinoid signaling produces analgesic andanti-inflammatory effects, it has been difficult to separate thesebeneficial effects from the unwanted side effects of these compounds. Analternative approach is to enhance the signaling of the endocannabinoidsystem by elevating the level of 2-AG, the endocannabinoid of highestabundance in the central nervous system (CNS) and gastrointestinaltract, which may be achieved by inhibition of MGL. Therefore, MGLinhibitors are potentially useful for the treatment of pain,inflammation and CNS disorders (Di Marzo et al., Curr Pharm Des, 2000,6, 1361-80; Shaveri et al., Brit J Pharmacol, 2007, 152, 624-632;McCarberg Bill et al., Amer J Ther, 2007, 14, 475-83), as well asglaucoma and disease states arising from elevated intraocular pressure(Njie, Ya Fatou; He, Fang; Qiao, Xhuanhong; Song, Zhoa-Hui, Exp. EyeRes., 2008, 87(2):106-14).

SUMMARY OF THE INVENTION

The present invention is directed to a method for treating, amelioratingor preventing a disease, syndrome, condition or disorder that isaffected by the inhibition of MGL (such as pain, the diseases that leadto such pain, inflammation and CNS disorders) comprising, consisting ofand/or consisting essentially of administering to a subject in needthereof, a therapeutically effective amount of a compound of Formula (I)

selected from the group consisting of

a compound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenoxymethyl, and R³ is2,2-dimethylpropyl;

a compound wherein W is N, R¹ is H,

is

X—Y—Z is —O—C(R²)═N—, and R² is cyclohexyl;

a compound wherein W is N, R¹ is H,

is

X—Y—Z is —O—C(R²)═N—, and R² is 3-fluorophenyl;

a compound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is 4-methylphenyl, and R³ is isobutyl;

a compound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenylmethyl, and R³ is isobutyl;

a compound wherein W is N, R¹ is H,

is

X—Y—Z is —O—C(R²)═N—, and R² is 4-fluorophenyl;

a compound wherein W is N, R¹ is H,

is

X—Y—Z is —O—C(R²)═N—, and R² is 4-methoxyphenyl;

a compound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is isobutyl, and R³ is isobutyl;

a compound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenoxymethyl, and R³ is isobutyl;

a compound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenyl, and R³ is 2,2-dimethylpropyl;

a compound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenoxymethyl, and R³ iscyclohexylmethyl;

a compound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is cyclopentylmethyl, and R³ is methyl;

a compound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenyl, and R³ is isobutyl;

a compound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is cyclohexylmethyl, and R³ is hydrogen;

a compound wherein W is N, R¹ is H,

is

X—Y—Z is —O—C(R²)═N—, and R² is 2-methoxyphenylmethyl;

a compound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is n-propyl, and R³ is methyl;

a compound wherein W is CH, R¹ is 2-methoxy,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenoxymethyl, and R³ is isobutyl;

a compound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenylmethyl, and R³ iscyclohexylmethyl;

a compound wherein W is N, R¹ is H,

is

X—Y—Z is —O—C(R²)═N—, and R² is t-butyl;

a compound wherein W is N, R¹ is H,

is

X—Y—Z is —O—C(R²)═N—, and R² is 3-methoxyphenyl;

a compound wherein W is CH, R¹ is 2-methoxy,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenylmethyl, and R³ is isobutyl;

a compound wherein W is CH, R¹ is 2-methoxy,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenoxymethyl, and R³ is2,2-dimethylpropyl;

a compound wherein W is CH, R¹ is 2-methoxy,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenylmethyl, and R³ iscyclohexylmethyl;

a compound wherein W is CH, R¹ is 2-methoxy,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenyl, and R³ is 2,2-dimethylpropyl;

a compound wherein W is CH, R¹ is 4-fluoro,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenyl, and R³ is 2,2-dimethylpropyl;

a compound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is t-butyl, and R³ is 2,2-dimethylpropyl;

a compound wherein W is N, R¹ is H,

is

X—Y—Z is —NH—C(R²)—C(R³)—, R² is 4-methylphenyl and R³ ismethoxy-methyl-carbonyl;

a compound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³), R² is n-propyl and R³ is cyclohexylmethyl;

and enantiomers, diastereomers, solvates and pharmaceutically acceptablesalts thereof.

The present invention is further directed to the use of a compound offormula (I) as herein defined, for the preparation of a medicament orpharmaceutical composition for the treatment, amelioration or preventionof a disease, syndrome, condition or disorder that is affected by theinhibition of MGL, in a subject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

In general, under standard nomenclature rules used throughout thisdisclosure, the terminal portion of the designated side chain isdescribed first followed by the adjacent functionality toward the pointof attachment. Thus, for example, a “C₁-C₆ alkylcarbonyl” substituentrefers to a group of the formula:

Unless otherwise noted, it is intended that the definition of anysubstituent or variable at a particular location in a molecule beindependent of its definitions elsewhere in that molecule. It isunderstood that substituents and substitution patterns on the compoundsof formula (I) can be selected by one of ordinary skill in the art toprovide compounds that are chemically stable and that can be readilysynthesized by techniques known in the art as well as those methods setforth herein.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

The term “therapeutically effective amount” as used herein, refers to anamount of an active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation or partial alleviation ofthe symptoms of the disease, syndrome, condition, or disorder beingtreated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in therapeuticallyeffective amounts, as well as any product that results, directly orindirectly, from combinations of the specified ingredients in thespecified amounts.

As used herein, unless otherwise noted, the terms “treating”,“treatment”, “ameliorating” and the like, shall include the managementand care of a subject or patient (preferably mammal, more preferablyhuman) for the purpose of combating a disease, condition, or disorderand includes the administration of a compound of the present inventionto prevent the onset of the symptoms or complications, alleviate thesymptoms or complications, or eliminate the disease, condition, ordisorder.

As used herein, unless otherwise noted, the terms “preventing” and“prevention” shall include (a) reduction in the frequency of one or moresymptoms; (b) reduction in the severity of one or more symptoms; (c) thedelay or avoidance of the development of additional symptoms; and/or (d)delay or avoidance of the development of the disorder or condition.

One skilled in the art will recognize that wherein the present inventionis directed to methods of prevention, a subject in need of thereof (i.e.a subject in need of prevention) shall include any subject or patient(preferably a mammal, more preferably a human) who has experienced orexhibited at least one symptom of the disorder, disease or condition tobe prevented. Further, a subject in need thereof may additionally be asubject (preferably a mammal, more preferably a human) who has notexhibited any symptoms of the disorder, disease or condition to beprevented, but who has been deemed by a physician, clinician or othermedical professional to be at risk of developing said disorder, diseaseor condition. For example, the subject may be deemed at risk ofdeveloping a disorder, disease or condition (and therefore in need ofprevention or preventive treatment) as a consequence of the subject'smedical history, including, but not limited to, family history,pre-disposition, co-existing (comorbid) disorders or conditions, genetictesting, and the like.

The term “MGL inhibitor” is intended to encompass a compound thatinteracts with MGL to substantially reduce or eliminate its catalyticactivity, thereby increasing the concentrations of its substrate(s). Theterm “MGL-modulated” is used to refer to the condition of being affectedby the modulation of the MGL enzyme including the condition of beingaffected by the inhibition of the MGL enzyme, such as, for example, painand the diseases that lead to such pain, inflammation and CNS disorders.

As used herein, unless otherwise noted, the term “affect” or “affected”(when referring to a disease, syndrome, condition or disorder that isaffected by inhibition of MGL) shall imply a reduction in the frequencyand/or severity of one or more symptoms or manifestations of saiddisease, syndrome, condition or disorder; and/or imply the prevention ofthe development of one or more symptoms or manifestations of saiddisease, syndrome, condition or disorder or the development of thedisease, condition, syndrome or disorder.

The compounds of formula (I) are useful in methods for treating,ameliorating and/or preventing a disease, a syndrome, a condition or adisorder that is affected by the inhibition of MGL. Such methodscomprise, consist of and/or consist essentially of administering to asubject, including an animal, a mammal, and a human in need of suchtreatment, amelioration and/or prevention, a therapeutically effectiveamount of a compound of formula (I), or an enantiomer, diastereomer,solvate or pharmaceutically acceptable salt thereof. In particular, thecompounds of formula (I) are useful for treating, ameliorating and/orpreventing pain; diseases, syndromes, conditions, or disorders causingsuch pain; inflammation and/or CNS disorders. More particularly, thecompounds of formula (I) are useful for treating, ameliorating and/orpreventing inflammatory pain, inflammatory hypersensitivity conditionsand/or neuropathic pain, comprising administering to a subject in needthereof a therapeutically effective amount of a compound of formula (I),as herein defined.

Examples of inflammatory pain include pain due to a disease, condition,syndrome, disorder, or a pain state including inflammatory boweldisease, visceral pain, migraine, post operative pain, osteoarthritis,rheumatoid arthritis, back pain, lower back pain, joint pain, abdominalpain, chest pain, labor, musculoskeletal diseases, skin diseases,toothache, pyresis, burn, sunburn, snake bite, venomous snake bite,spider bite, insect sting, neurogenic bladder, interstitial cystitis,urinary tract infection, rhinitis, contact dermatitis/hypersensitivity,itch, eczema, pharyngitis, mucositis, enteritis, irritable bowelsyndrome, cholecystitis, pancreatitis, postmastectomy pain syndrome,menstrual pain, endometriosis, pain due to physical trauma, headache,sinus headache, tension headache, or arachnoiditis.

One type of inflammatory pain is inflammatoryhyperalgesia/hypersensitivity. Examples of inflammatory hyperalgesiainclude a disease, syndrome, condition, disorder, or pain stateincluding inflammation, osteoarthritis, rheumatoid arthritis, back pain,joint pain, abdominal pain, musculoskeletal diseases, skin diseases,post operative pain, headaches, toothache, burn, sunburn, insect sting,neurogenic bladder, urinary incontinence, interstitial cystitis, urinarytract infection, cough, asthma, chronic obstructive pulmonary disease,rhinitis, contact dermatitis/hypersensitivity, itch, eczema,pharyngitis, enteritis, irritable bowel syndrome, inflammatory boweldiseases including Crohn's Disease, ulcerative colitis, urinaryincontinence, benign prostatic hypertrophy, cough, asthma, rhinitis,nasal hypersensitivity, itch, contact dermititis and/or dermal allergyand chronic obstructive pulmonary disease.

In an embodiment, the present invention is directed to a method fortreating, ameliorating and/or preventing inflammatory visceralhyperalgesia in which a enhanced visceral irritability exists,comprising, consisting of, and/or consisting essentially of the step ofadministering to a subject in need of such treatment a therapeuticallyeffective amount of a compound, salt or solvate of formula (I). In afurther embodiment, the present invention is directed to a method fortreating inflammatory somatic hyperalgesia in which a hypersensitivityto thermal, mechanical and/or chemical stimuli exists, comprisingadministering to a mammal in need of such treatment a therapeuticallyeffective amount of a compound of formula (I) or an enantiomer,diastereomer, solvate or pharmaceutically acceptable salt thereof.

A further embodiment of the present invention is directed to a methodfor treating, ameliorating and/or preventing neuropathic pain. Examplesof a neuropathic pain include pain due to a disease, syndrome,condition, disorder, or pain state including cancer, neurologicaldisorders, spine and peripheral nerve surgery, brain tumor, traumaticbrain injury (TBI), spinal cord trauma, chronic pain syndrome,fibromyalgia, chronic fatigue syndrome, lupus, sarcoidosis, peripheralneuropathy, bilateral peripheral neuropathy, diabetic neuropathy,central pain, neuropathies associated with spinal cord injury, stroke,amyotrophic lateral sclerosis (ALS), Parkinson's disease, multiplesclerosis, sciatic neuritis, mandibular joint neuralgia, peripheralneuritis, polyneuritis, stump pain, phantom limb pain, bony fractures,oral neuropathic pain, Charcot's pain, complex regional pain syndrome Iand II (CRPS I/II), radiculopathy, Guillain-Barre syndrome, meralgiaparesthetica, burning-mouth syndrome, optic neuritis, postfebrileneuritis, migrating neuritis, segmental neuritis, Gombault's neuritis,neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculateneuralgia, glossopharyngial neuralgia, migrainous neuralgia, idiopathicneuralgia, intercostals neuralgia, mammary neuralgia, Morton'sneuralgia, nasociliary neuralgia, occipital neuralgia, postherpeticneuralgia, causalgia, red neuralgia, Sluder's neuralgia, splenopalatineneuralgia, supraorbital neuralgia, trigeminal neuralgia, vulvodynia, orvidian neuralgia.

One type of neuropathic pain is neuropathic cold allodynia, which can becharacterized by the presence of a neuropathy-associated allodynic statein which a hypersensitivity to cooling stimuli exists. Examples ofneuropathic cold allodynia include allodynia due to a disease,condition, syndrome, disorder or pain state including neuropathic pain(neuralgia), pain arising from spine and peripheral nerve surgery ortrauma, traumatic brain injury (TBI), trigeminal neuralgia, postherpeticneuralgia, causalgia, peripheral neuropathy, diabetic neuropathy,central pain, stroke, peripheral neuritis, polyneuritis, complexregional pain syndrome I and II (CRPS I/II) and radiculopathy.

In a further embodiment, the present invention is directed to a methodfor treating, ameliorating and/or preventing neuropathic cold allodyniain which a hypersensitivity to a cooling stimuli exists, comprising,consisting of, and/or consisting essentially of the step ofadministering to a subject in need of such treatment a therapeuticallyeffective amount of a compound of formula (I) or an enantiomer,diastereomer, solvate or pharmaceutically acceptable salt thereof.

In a further embodiment, the present invention is directed to a methodfor treating, ameliorating and/or preventing CNS disorders. Examples ofCNS disorders include anxieties, such as social anxiety, post-traumaticstress disorder, phobias, social phobia, special phobias, panicdisorder, obsessive-compulsive disorder, acute stress, disorder,separation anxiety disorder, and generalized anxiety disorder, as wellas depression, such as major depression, bipolar disorder, seasonalaffective disorder, post natal depression, manic depression, and bipolardepression.

The present invention is directed to methods of treating, amelioratingand/or preventing a disorder, syndrome, condition or disease that isaffected by the inhibition of MGL, comprising, consisting of orconsisting essentially of administering to a subject in need thereof atherapeutically effective amount of a compound of formula (I)

selected from the group consisting of

-   [1-(2,2-Dimethyl-propyl)-2-phenoxymethyl-1H-indol-5-yl]-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #1)-   (2-Cyclohexyl-benzooxazol-6-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #2)-   [2-(3-Fluoro-phenyl)-benzooxazol-7-yl]-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #3)-   (1-Isobutyl-2-p-tolyl-1H-indol-5-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #4)-   [1-Isobutyl-2-(4-methyl-benzyl)-1H-indol-5-yl]-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #5)-   [2-(4-Fluoro-phenyl)-benzooxazol-7-yl]-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #6)-   [2-(4-Methoxy-phenyl)-benzooxazol-7-yl]-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #7)-   (1,2-Diisobutyl-1H-indol-5-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #8)-   (1-Isobutyl-2-phenoxymethyl-1H-indol-5-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #9)-   [1-(2,2-Dimethyl-propyl)-2-phenyl-1H-indol-5-yl]-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #10)-   (1-Cyclohexylmethyl-2-phenoxymethyl-1H-indol-5-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #11)-   (2-Cyclopentylmethyl-1-methyl-1H-indol-5-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #12)-   (1-Isobutyl-2-phenyl-1H-indol-5-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #13)-   (2-Cyclohexylmethyl-1H-indol-5-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #14)-   [2-(2-Methoxy-benzyl)-benzooxazol-5-yl]-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #15)-   (2-Ethyl-1-methyl-1H-indol-5-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #16)-   (1-Isobutyl-2-phenoxymethyl-1H-indol-5-yl)-{3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-azetidin-1-yl}-methanone;    (Compound #17)-   (2-Benzyl-1-cyclohexylmethyl-1H-indol-5-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #18)-   (2-tert-Butyl-benzooxazol-6-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #19)-   [2-(3-Methoxy-phenyl)-benzooxazol-5-yl]-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #20)-   (2-Benzyl-1-isobutyl-1H-indol-5-yl)-{3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-azetidin-1-yl}-methanone;    (Compound #21)-   [1-(2,2-Dimethyl-propyl)-2-phenoxymethyl-1H-indol-5-yl]-{3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-azetidin-1-yl}-methanone;    (Compound #22)-   (2-Benzyl-1-cyclohexylmethyl-1H-indol-5-yl)-{3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-azetidin-1-yl}-methanone;    (Compound #23)-   [1-(2,2-Dimethyl-propyl)-2-phenyl-1H-indol-5-yl]-{3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-azetidin-1-yl}-methanone;    (Compound #24)-   [1-(2,2-Dimethyl-propyl)-2-phenyl-1H-indol-5-yl]-{3-[4-(4-fluoro-phenyl)-piperazin-1-yl]-azetidin-1-yl}-methanone;    (Compound #25)-   [2-tert-Butyl-1-(2,2-dimethyl-propyl)-1H-indol-5-yl]-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #26)-   2-Methoxy-1-{5-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidine-1-carbonyl]-2-p-tolyl-1H-indol-3-yl}-ethanone;    (Compound #27)-   (1-Cyclohexylmethyl-2-propyl-1H-indol-5-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #28)

and enantiomers, diastereomers, solvates and pharmaceutically acceptablesalts thereof. Preferably, the disease, syndrome, condition or disorderthat is affected by inhibition of MGL is selected from the groupconsisting of pain, inflammatory pain, inflammatory hypersensitivityconditions and neuropathic pain, as herein defined.

In an embodiment, the present invention is directed to treating,ameliorating or preventing a disease, syndrome, condition or disorderthat is affected by inhibition of MGL, comprising administering to asubject in need thereof, a therapeutically effective amount of acompound of formula (Ia)

or an enantiomer, diastereomer, solvate or pharmaceutically acceptablesalt thereof, wherein R¹, W, and —X—Y—Z— are as herein defined. Inanother embodiment, the present invention is directed to treating,ameliorating or preventing a disease, syndrome, condition or disorderthat is affected by inhibition of MGL, comprising administering to asubject in need thereof, a therapeutically effective amount of acompound of formula (Ib)

or an enantiomer, diastereomer, solvate or pharmaceutically acceptablesalt thereof, wherein R¹, W, and —X—Y—Z— are as herein defined. In yetanother embodiment, the present invention is directed to treating,ameliorating or preventing a disease, syndrome, condition or disorderthat is affected by inhibition of MGL, comprising administering to asubject in need thereof, a therapeutically effective amount of acompound of formula (Ic)

or an enantiomer, diastereomer, solvate or pharmaceutically acceptablesalt thereof, wherein R¹, W, and —X—Y—Z— are as herein defined.

In another embodiment, the present invention is directed to treating,ameliorating or preventing a disease, syndrome, condition or disorderthat is affected by inhibition of MGL, comprising administering to asubject in need thereof, a therapeutically effective amount of acompound selected from the group consisting of

-   [1-(2,2-Dimethyl-propyl)-2-phenoxymethyl-1H-indol-5-yl]-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #1)-   (2-Cyclohexyl-benzooxazol-6-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #2)-   [2-(3-Fluoro-phenyl)-benzooxazol-7-yl]-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #3)-   (1-Isobutyl-2-p-tolyl-1H-indol-5-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #4)-   [1-Isobutyl-2-(4-methyl-benzyl)-1H-indol-5-yl]-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #5)-   [2-(4-Fluoro-phenyl)-benzooxazol-7-yl]-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #6)-   [2-(4-Methoxy-phenyl)-benzooxazol-7-yl]-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #7)-   (1,2-Diisobutyl-1H-indol-5-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #8)-   (1-Isobutyl-2-phenoxymethyl-1H-indol-5-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #9)-   [1-(2,2-Dimethyl-propyl)-2-phenyl-1H-indol-5-yl]-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #10)-   (1-Cyclohexylmethyl-2-phenoxymethyl-1H-indol-5-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #11)-   (2-Cyclopentylmethyl-1-methyl-1H-indol-5-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #12)-   (1-Isobutyl-2-phenyl-1H-indol-5-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #13)-   (2-Cyclohexylmethyl-1H-indol-5-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #14)-   [2-(2-Methoxy-benzyl)-benzooxazol-5-yl]-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #15)-   (2-Ethyl-1-methyl-1H-indol-5-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #16)-   (1-Isobutyl-2-phenoxymethyl-1H-indol-5-yl)-{3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-azetidin-1-yl}-methanone;    (Compound #17)-   (2-Benzyl-1-cyclohexylmethyl-1H-indol-5-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #18)

and enantiomers, diastereomers, solvates and pharmaceutically acceptablesalt thereof.

In another embodiment, the present invention is directed to the use of acompound selected from the group consisting of

-   [1-(2,2-Dimethyl-propyl)-2-phenoxymethyl-1H-indol-5-yl]-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #1)-   [2-(3-Fluoro-phenyl)-benzooxazol-7-yl]-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #3)-   (1-Isobutyl-2-p-tolyl-1H-indol-5-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #4)-   [1-Isobutyl-2-(4-methyl-benzyl)-1H-indol-5-yl]-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #5)-   [2-(4-Fluoro-phenyl)-benzooxazol-7-yl]-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #6)-   [2-(4-Methoxy-phenyl)-benzooxazol-7-yl]-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #7)-   (1-Isobutyl-2-phenoxymethyl-1H-indol-5-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #9)-   [1-(2,2-Dimethyl-propyl)-2-phenyl-1H-indol-5-yl]-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #10)-   (1-Cyclohexylmethyl-2-phenoxymethyl-1H-indol-5-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #11)-   (1-Isobutyl-2-phenyl-1H-indol-5-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #13)-   (2-Benzyl-1-cyclohexylmethyl-1H-indol-5-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #18)-   (1-Cyclohexylmethyl-2-propyl-1H-indol-5-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #28)

and enantiomers, diastereomers, solvates and pharmaceutically acceptablesalt thereof.

In another embodiment, the present invention is directed to treating,ameliorating or preventing a disease, syndrome, condition or disorderthat is affected by inhibition of MGL, comprising administering to asubject in need thereof, a therapeutically effective amount of acompound selected from the group consisting of

-   (2-Cyclohexyl-benzooxazol-6-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #2)-   [2-(3-Fluoro-phenyl)-benzooxazol-7-yl]-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #3)-   [1-Isobutyl-2-(4-methyl-benzyl)-1H-indol-5-yl]-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #5)-   [2-(4-Methoxy-phenyl)-benzooxazol-7-yl]-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #7)-   [1-(2,2-Dimethyl-propyl)-2-phenyl-1H-indol-5-yl]-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #10)-   (1-Cyclohexylmethyl-2-phenoxymethyl-1H-indol-5-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #11)-   (2-Cyclopentylmethyl-1-methyl-1H-indol-5-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #12)-   (1-Isobutyl-2-phenyl-1H-indol-5-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #13)-   (2-Benzyl-1-cyclohexylmethyl-1H-indol-5-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #18)-   [2-(3-Methoxy-phenyl)-benzooxazol-5-yl]-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #20)-   (2-Benzyl-1-cyclohexylmethyl-1H-indol-5-yl)-{3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-azetidin-1-yl}-methanone;    (Compound #23)-   2-Methoxy-1-{5-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidine-1-carbonyl]-2-p-tolyl-1H-indol-3-yl}-ethanone;    (Compound #27)-   (1-Cyclohexylmethyl-2-propyl-1H-indol-5-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #28)

and enantiomers, diastereomers, solvates and pharmaceutically acceptablesalt thereof.

In another embodiment, the present invention is directed to treating,ameliorating or preventing a disease, syndrome, condition or disorderthat is affected by inhibition of MGL, comprising administering to asubject in need thereof, a therapeutically effective amount of acompound selected from the group consisting of

-   (2-Cyclohexyl-benzooxazol-6-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #2)-   [2-(3-Fluoro-phenyl)-benzooxazol-7-yl]-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #3)-   [2-(4-Fluoro-phenyl)-benzooxazol-7-yl]-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #6)-   (2-tert-Butyl-benzooxazol-6-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone;    (Compound #19)

and enantiomers, diastereomers, solvates and pharmaceutically acceptablesalt thereof.

In another embodiment, the present invention is directed to the use ofany single compound or subset of compounds selected from the compoundslisted in Tables 1-3 below, or an enantiomer, diastereomer, solvate orpharmaceutically acceptable salt thereof; for the treatment,amelioration or prevention or a disease, syndrome, condition or disorderthat is affected by the inhibition of MGL, in a subject in need thereof.The compounds of formula (I) of the present invention are as listed inTables 1-3, below.

TABLE 1 Compounds of Formula (Ia)

Cmpd No. W R¹ X—Y—Z R² 3 N H —O—C(R²)═N— 3-fluorophenyl 6 N H—O—C(R²)═N— 4-fluorophenyl 7 N H —O—C(R²)═N— 4-methoxyphenyl

TABLE 2 Compounds of Formula (Ib)

Cmpd No. W R¹ X Y Z R² R³  1 N H —CH—C(R²)—N(R³)— phenoxymethyl 2,2-dimethylpropyl  2 N H —O—C(R²)═N— cyclohexyl  4 N H —CH—C(R²)—N(R³)—4-methylphenyl isobutyl  5 N H —CH—C(R²)—N(R³)— phenylmethyl isobutyl  8N H —CH—C(R²)—N(R³)— isobutyl isobutyl  9 N H —CH—C(R²)—N(R³)—phenoxymethyl isobutyl 10 N H —CH—C(R²)—N(R³)— phenyl 2,2-dimethylpropyl 11 N H —CH—C(R²)—N(R³)— phenoxymethyl cyclohexyl- methyl12 N H —CH—C(R²)—N(R³)— cyclopentyl- methyl methyl 13 N H—CH—C(R²)—N(R³)— phenyl isobutyl 14 N H —CH—C(R²)—N(R³)— cyclohexy-hydrogen lmethyl 16 N H —CH—C(R²)—N(R³)— n-propyl methyl 17 CH 2-methoxy—CH—C(R²)—N(R³)— phenoxymethyl isobutyl 18 N H —CH—C(R²)—N(R³)—phenylmethyl cyclohexyl- methyl 19 N H —O—C(R²)═N— t-butyl 21 CH2-methoxy —CH—C(R²)—N(R³)— phenylmethyl isobutyl 22 CH 2-methoxy—CH—C(R²)—N(R³)— phenoxymethyl 2,2-dimethyl- propyl 23 CH 2-methoxy—CH—C(R²)—N(R³)— phenylmethyl cyclohexyl- methyl 24 CH 2-methoxy—CH—C(R²)—N(R³)— phenyl 2,2-dimethyl- propyl 25 CH 4-fluoro—CH—C(R²)—N(R³)— phenyl 2,2-dimethyl- propyl 26 N H —CH—C(R²)—N(R³)—t-butyl 2,2- dimethypropyl 28 N H —CH—C(R²)—N(R³)— n-propyl cyclohexyl-methyl

TABLE 3 Compounds of Formula (Ic)

Cmpd No. W R¹ X Y Z R² R³ 15 N H —O—C(R²)═N— 2-methoxy- phenylmethyl 20N H —O—C(R²)═N— 3-methoxy- phenyl 27 N H —NH—C(R²)—C(R³)— 4-methylphenylmethoxy- methyl- carbonyl

In an embodiment, the present invention is directed to treating,ameliorating or preventing a disease, syndrome, condition or disorderthat is affected by inhibition of MGL, wherein the disease, syndrome,condition or disorder that is affected by inhibition of MGL is selectedfrom the group consisting of inflammatory pain and neuropathic pain;comprising administering to a subject in need thereof (including amammal and/or human), a therapeutically effective amount of a compoundof formula (I)

selected from the group as herein defined; and enantiomers,diastereomers, solvates and pharmaceutically acceptable salt thereof.

In an embodiment, the present invention is directed to treating,ameliorating or preventing inflammatory pain; comprising administeringto a subject in need thereof (including a mammal and/or human), atherapeutically effective amount of a compound of formula (I)

selected from the group as herein defined; and enantiomers,diastereomers, solvates and pharmaceutically acceptable salt thereof. Inanother embodiment of the present invention, the inflammatory pain isselected from the group consisting of visceral pain and inflammatoryhyeralgesia, preferably visceral pain.

In an embodiment, the present invention is directed to treating,ameliorating or preventing inflammatory hyperalgesia, comprisingadministering to a subject in need thereof (including a mammal and/orhuman), a therapeutically effective amount of a compound of formula (I)

selected from the group as herein defined; and enantiomers,diastereomers, solvates and pharmaceutically acceptable salt thereof. Inanother embodiment of the present invention, the inflammatoryhyperalgesia is ulcerative colitis.

In an embodiment, the present invention is directed to treating,ameliorating or preventing neuropathic pain, comprising administering toa subject in need thereof (including a mammal and/or human), atherapeutically effective amount of a compound of formula (I)

selected from the group as herein defined; and enantiomers,diastereomers, solvates and pharmaceutically acceptable salt thereof. Inanother embodiment of the present invention, the neuropathic pain isneuropathic cold allodynia.

For use in medicine, salts of compounds of formula (I) refer tonon-toxic “pharmaceutically acceptable salts.” Other salts may, however,be useful in the preparation of compounds of formula (I) or of theirpharmaceutically acceptable salts thereof. Suitable pharmaceuticallyacceptable salts of compounds of formula (I) include acid addition saltswhich can, for example, be formed by mixing a solution of the compoundwith a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of formula (I)carry an acidic moiety, suitable pharmaceutically acceptable saltsthereof may include alkali metal salts, such as sodium or potassiumsalts; alkaline earth metal salts, such as calcium or magnesium salts;and salts formed with suitable organic ligands, such as quaternaryammonium salts. Thus, representative pharmaceutically acceptable saltsinclude acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,bitartrate, borate, bromide, calcium edetate, camsylate, carbonate,chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate,pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate,tosylate, triethiodide and valerate.

Representative acids and bases that may be used in the preparation ofpharmaceutically acceptable salts include acids such as acetic acid,2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginicacid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoicacid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid,2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaricacid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronicacid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hippuricacid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid,(±)-DL-lactic acid, lactobionic acid, maleic acid, (−)-L-malic acid,malonic acid, (±)-DL-mandelic acid, methanesulfonic acid,naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid,1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid,orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid,L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebaicacid, stearic acid, succinic acid, sulfuric acid, tannic acid,(+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid andundecylenic acid; and bases including ammonia, L-arginine, benethamine,benzathine, calcium hydroxide, choline, deanol, diethanolamine,diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine,N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesiumhydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide,triethanolamine, tromethamine and zinc hydroxide.

Embodiments of the present invention include prodrugs of compounds offormula (I). In general, such prodrugs will be functional derivatives ofthe compounds that are readily convertible in vivo into the requiredcompound. Thus, in the methods of treating or preventing embodiments ofthe present invention, the term “administering” encompasses thetreatment or prevention of the various diseases, conditions, syndromesand disorders described with the compound specifically disclosed or witha compound that may not be specifically disclosed, but which converts tothe specified compound in vivo after administration to a patient.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in “Design of Prodrugs”,ed. H. Bundgaard, Elsevier, 1985.

Where the compounds according to embodiments of this invention have atleast one chiral center, they may accordingly exist as enantiomers.Where the compounds possess two or more chiral centers, they mayadditionally exist as diastereomers. It is to be understood that allsuch isomers and mixtures thereof are encompassed within the scope ofthe present invention. Furthermore, some of the crystalline forms forthe compounds may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compoundsmay form solvates with water (i.e., hydrates) or common organicsolvents, and such solvates are also intended to be encompassed withinthe scope of this invention. The skilled artisan will understand thatthe term compound as used herein, is meant to include solvated compoundsof Formula (I).

Where the processes for the preparation of the compounds according tocertain embodiments of the invention give rise to mixture ofstereoisomers, these isomers may be separated by conventional techniquessuch as preparative chromatography. The compounds may be prepared inracemic form, or individual enantiomers may be prepared either byenantiospecific synthesis or by resolution. The compounds may, forexample, be resolved into their component enantiomers by standardtechniques, such as the formation of diastereomeric pairs by saltformation with an optically active acid, such as(−)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acidfollowed by fractional crystallization and regeneration of the freebase. The compounds may also be resolved by formation of diastereomericesters or amides, followed by chromatographic separation and removal ofthe chiral auxiliary. Alternatively, the compounds may be resolved usinga chiral HPLC column.

One embodiment of the present invention is directed to a composition,including a pharmaceutical composition, comprising, consisting of,and/or consisting essentially of the (+)-enantiomer of a compound offormula (I) wherein said composition is substantially free from the(−)-isomer of said compound. In the present context, substantially freemeans less than about 25%, preferably less than about 10%, morepreferably less than about 5%, even more preferably less than about 2%and even more preferably less than about 1% of the (−)-isomer calculatedas

${\% ( + )\text{-}{enantiomer}} = {\frac{\left( {{{mass}( + )}\text{-}{enantiomer}} \right)}{\left( {{{mass}( + )}\text{-}{enantiomer}} \right) + \left( {{{mass}( - )}\text{-}{enantiomer}} \right)} \times 100.}$

Another embodiment of the present invention is a composition, includinga pharmaceutical composition, comprising, consisting of, and consistingessentially of the (−)-enantiomer of a compound of formula (I) whereinsaid composition is substantially free from the (+)-isomer of saidcompound. In the present context, substantially free from means lessthan about 25%, preferably less than about 10%, more preferably lessthan about 5%, even more preferably less than about 2% and even morepreferably less than about 1% of the (+)-isomer calculated as

${\% ( - )\text{-}{enantiomer}} = {\frac{\left( {{{mass}( - )}\text{-}{enantiomer}} \right)}{\left( {{{mass}( + )}\text{-}{enantiomer}} \right) + \left( {{{mass}( - )}\text{-}{enantiomer}} \right)} \times 100.}$

During any of the processes for preparation of the compounds of thevarious embodiments of the present invention, it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, Second Edition, J. F. W. McOmie, Plenum Press, 1973;T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis,John Wiley & Sons, 1991; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, Third Edition, John Wiley & Sons, 1999. Theprotecting groups may be removed at a convenient subsequent stage usingmethods known from the art.

Even though the compounds of embodiments of the present invention(including their pharmaceutically acceptable salts and pharmaceuticallyacceptable solvates) can be administered alone, they will generally beadministered in admixture with a pharmaceutically acceptable carrier, apharmaceutically acceptable excipient and/or a pharmaceuticallyacceptable diluent selected with regard to the intended route ofadministration and standard pharmaceutical or veterinary practice. Thus,particular embodiments of the present invention are directed topharmaceutical and veterinary compositions comprising compounds offormula (I) and at least one pharmaceutically acceptable carrier,pharmaceutically acceptable excipient, and/or pharmaceuticallyacceptable diluent.

By way of example, in the pharmaceutical compositions of embodiments ofthe present invention, the compounds of formula (I) may be admixed withany suitable binder(s), lubricant(s), suspending agent(s), coatingagent(s), solubilizing agent(s), and combinations thereof.

Solid oral dosage forms, such as tablets or capsules, containing thecompounds of the present invention may be administered in at least onedosage form at a time, as appropriate. It is also possible to administerthe compounds in sustained release formulations.

Additional oral forms in which the present inventive compounds may beadministered include elixirs, solutions, syrups, and suspensions; eachoptionally containing flavoring agents and coloring agents.

Alternatively, compounds of formula (I) can be administered byinhalation (intratracheal or intranasal) or in the form of a suppositoryor pessary, or they may be applied topically in the form of a lotion,solution, cream, ointment or dusting powder. For example, they can beincorporated into a cream comprising, consisting of, and/or consistingessentially of an aqueous emulsion of polyethylene glycols or liquidparaffin. They can also be incorporated, at a concentration of betweenabout 1% and about 10% by weight of the cream, into an ointmentcomprising, consisting of, and/or consisting essentially of a white waxor white soft paraffin base together with any stabilizers andpreservatives as may be required. An alternative means of administrationincludes transdermal administration by using a skin or transdermalpatch.

The pharmaceutical compositions of the present invention (as well as thecompounds of the present invention alone) can also be injectedparenterally, for example intracavernosally, intravenously,intramuscularly, subcutaneously, intradermally or intrathecally. In thiscase, the compositions will also include at least one of a suitablecarrier, a suitable excipient, and a suitable diluent.

For parenteral administration, the pharmaceutical compositions of thepresent invention are best used in the form of a sterile aqueoussolution that may contain other substances, for example, enough saltsand monosaccharides to make the solution isotonic with blood.

For buccal or sublingual administration, the pharmaceutical compositionsof the present invention may be administered in the form of tablets orlozenges, which can be formulated in a conventional manner.

By way of further example, pharmaceutical compositions containing atleast one of the compounds of formula (I) can be prepared by mixing thecompound(s) with a pharmaceutically acceptable carrier, apharmaceutically acceptable diluent, and/or a pharmaceuticallyacceptable excipient according to conventional pharmaceuticalcompounding techniques. The carrier, excipient, and diluent may take awide variety of forms depending upon the desired route of administration(e.g., oral, parenteral, etc.). Thus for liquid oral preparations, suchas suspensions, syrups, elixirs and solutions, suitable carriers,excipients and diluents include water, glycols, oils, alcohols,flavoring agents, preservatives, stabilizers, coloring agents and thelike; for solid oral preparations, such as powders, capsules andtablets, suitable carriers, excipients and diluents include starches,sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Solid oral preparations also may beoptionally coated with substances, such as, sugars, or beenterically-coated so as to modulate the major site of absorption anddisintegration. For parenteral administration, the carrier, excipientand diluent will usually include sterile water, and other ingredientsmay be added to increase solubility and preservation of the composition.Injectable suspensions or solutions may also be prepared utilizingaqueous carriers along with appropriate additives, such as solubilizersand preservatives.

A therapeutically effective amount of a compound of formula (I) or apharmaceutical composition thereof includes a dose range from about 0.1mg to about 3000 mg, or any amount or range therein, in particular fromabout 1 mg to about 1000 mg, or any amount or range therein, moreparticularly, from about 10 mg to about 500 mg, or any amount or rangetherein, of ingredient compound of formula (I) in a regimen of about 1to 4 times per day for an average (70 kg) human; although, it isapparent to one skilled in the art that the therapeutically effectiveamount for a compound of formula (I) will vary as will the diseases,syndromes, conditions, and disorders being treated.

For oral administration, a pharmaceutical composition is preferablyprovided in the form of tablets containing about 0.01, about 10, about50, about 100, about 150, about 200, about 250, and about 500 milligramsof a compound of formula (I).

Advantageously, a compound of formula (I) may be administered in asingle daily dose, or the total daily dosage may be administered individed doses of two, three and four times daily.

Optimal dosages of a compound of formula (I) to be administered may bereadily determined and will vary with the particular compound used, themode of administration, the strength of the preparation, and theadvancement of the disease, syndrome, condition, or disorder. Inaddition, factors associated with the particular subject being treated,including subject age, weight, diet and time of administration, willresult in the need to adjust the dose to achieve an appropriatetherapeutic level and desired therapeutic effect. The above dosages arethus exemplary of the average case. There can be, of course, individualinstances wherein higher or lower dosage ranges are merited, and suchare within the scope of this invention.

One skilled in the art will recognize that, both in vivo and in vitrotrials using suitable, known and generally accepted cell and/or animalmodels are predictive of the ability of a test compound to treat orprevent a given disorder. One skilled in the art will further recognizethat human clinical trails including first-in-human, dose ranging andefficacy trials, in healthy patients and/or those suffering from a givendisorder, may be completed according to methods well known in theclinical and medical arts.

A compound of formula (I) may be administered in any of the foregoingcompositions and dosage regimens or by means of those compositions anddosage regimens established in the art whenever use of a compound offormula (I) is required for a subject in need thereof.

General Synthetic Methods

Representative compounds of the present invention may be synthesized inaccordance with the general synthetic methods described below andillustrated in the schemes that follow. Since the schemes are anillustration, the invention should not be construed as being limited bythe specific chemical reactions and specific conditions described in theschemes and examples. The various starting materials used in the schemesare commercially available or may be prepared by methods well within theskill of persons versed in the art. The variables are as defined hereinand within the skill of persons versed in the art.

Abbreviations used in the specification, particularly the Schemes andExamples, are as follows:

-   -   DCC=N,N-Dicyclohexylcarbodiimide    -   DCM=Dichloromethane    -   DIPEA or DIEA=Diisopropylethylamine    -   DMF=N,N-Dimethylformamide    -   DMSO=Dimethylsulfoxide    -   EDTA=Ethylenediaminetetraacetic acid    -   EtOAc=Ethyl Acetate    -   HATU=O-(7-Azabenzotriazol-1-yl)-N,N,N″,N″-Tetramethyl Uronium        Hexafluorophosphate    -   HBTU=O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate    -   HEPES=4-(2-Hydroxyethyl)-1-piperazineethane sulfonic acid    -   TEA=Triethylamine    -   TFA=Trifluoroacetic Acid    -   THF=Tetrahydrofuran

The compounds of Formula (I) of the present invention may be preparedaccording to the process as outlined in Scheme 1, below.

Accordingly, a suitably substituted compound of formula (V), a knowncompound or compound prepared by known methods, is reacted with asuitably substituted compound of formula (VI), wherein PG¹ is a suitablyselected nitrogen protecting group such as —CH(phenyl)₂, benzyl,t-butyl, methyl, and the like, preferably —CH(phenyl)₂, a known compoundor compound prepared by known methods; in the presence of an organicbase such as DIPEA, pyridine, and the like (preferably not TEA); in anorganic solvent such as acetonitrile, THF, DCM, and the like; preferablyat a temperature in the range of from about 50° C. to about 90° C.; toyield the corresponding compound of formula (VII).

The compound of formula (VII) is de-protected according to knownmethods, to yield the corresponding compound of formula (VIII). Forexample, wherein PG¹ is —CH(phenyl)₂, the compound of formula (VII) isde-protected by reacting with 1-chloroethyl chloroformate, in an organicsolvent such as dichloromethane, and then refluxed in an organic solventsuch as methanol, to yield the corresponding compound of formula (VIII).

The compound of formula (VIII) is reacted with a suitably substitutedcompound of formula (IX), wherein LG¹ is selected from the groupconsisting of —C(O)Cl and C(O)OH, and wherein LG¹ is bound at thedesired bonding position on benzene ring of the benzo-fused portion ofthe compound of formula (IX), a known compound or compound prepared byknown methods, in the presence of a suitably selected coupling agentsuch as HATU, HBTU, DCC, and the like; in the presence of a suitablyselected organic base such as DIPEA, TEA, pyridine, and the like; in anorganic solvent such as acetonitrile, DMF, DCM, and the like; to yieldthe corresponding compound of formula (I).

The following Examples are set forth to aid in the understanding of theinvention, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

In the Examples which follow, some synthesis products are listed ashaving been isolated as a residue. It will be understood by one ofordinary skill in the art that the term “residue” does not limit thephysical state in which the product was isolated and may include, forexample, a solid, an oil, a foam, a gum, a syrup, and the like.

Example 1(2-Cyclohexyl-benzooxazol-6-yl)-[3-(4-pyridin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone

STEP A: 2-Cyclohexyl-benzooxazole-6-carboxylic acid

To a solution of 4-amino-3-hydroxy-benzoic acid methyl ester (5 g, 29.91mmol) in CH₃OH (150 mL) was added cyclohexanecarbaldehyde (3.6 mL, 29.91mmol) at room temperature. The resulting mixture was stirred at roomtemperature for 2 h. The solvent was removed by evaporation and CH₃CN(150 mL) was added to the residue. Lead (IV) acetate (13.26 g, 29.91mmol) was added as one portion under N₂ and the resulting mixture wasrefluxed for 10 min. After cooling, the resulting solid was filtered andwashed with CH₃CN. To the filtrate was then added 3N NaOH (40 mL). Theresulting mixture was stirred at 50° C. for 18 h. The solvent wasremoved by evaporation and the resulting residue was purified by flashchromatography on silica gel to yield2-cyclohexyl-benzooxazole-6-carboxylic acid. MS m/z (M+H⁺) 246.2.

STEP B:(2-Cyclohexyl-benzooxazol-6-yl)-(3-hydroxy-azetidin-1-yl)-methanone

To a solution of 2-cyclohexyl-benzooxazole-6-carboxylic acid (0.47 g,1.9 mmol) and HBTU (0.94 g, 2.5 mmol) in DMF (10 mL) was added DIPEA(1.4 mL, 7.6 mmol). The resulting mixture was stirred at roomtemperature for 10 min, and then the hydrochloride salt of azetidin-3-ol(0.452 g, 4.7 mmol) was added. The resulting mixture was stirred at roomtemperature for 1 h, and then purified by reverse phase liquidchromatography. Fractions containing product were lyophilized to yield(2-cyclohexyl-benzooxazol-6-yl)-(3-hydroxy-azetidin-1-yl)-methanone. MSm/z (M+H⁺) 301.

STEP C:2-Cyclohexyl-6-{[3-(4-pyridin-2-ylpiperazin-1-yl)azetidin-1-yl]carbonyl}-1,3-benzoxazole

Methanesulfonyl chloride (0.152 mL, 1.9 mmol) was added dropwise to asolution of(2-cyclohexyl-benzooxazol-6-yl)-(3-hydroxy-azetidin-1-yl)-methanone(0.48 g, 1.6 mmol) and DIPEA (0.558 mL, 3.2 mmol) in DCM (20 mL) at −40°C. under nitrogen. Immediately following the addition, the cooling bathwas removed and the mixture slowly warmed to room temperature. Theresulting mixture was then washed with water, dried using magnesiumsulfate, filtered, and the solvent removed under reduced pressure. Theresulting residue was dissolved in acetonitrile (1 mL). DIPEA (0.41 mL,2.4 mmol) and N-(2-pyridyl)piperazine (1.6 mmol) were added. Theresulting mixture was then microwaved at 160° C. for 4 hours. DMF (3 mL)was added to the resulting mixture, which was then purified by reversephase liquid chromatography. The fractions containing product werediluted with 1N HCl (5 mL) and then lyophilized to yield2-cyclohexyl-6-{[3-(4-pyridin-2-ylpiperazin-1-yl)azetidin-1-yl]carbonyl}-1,3-benzoxazoleas its corresponding hydrochloride salt.

¹H NMR (400 MHz, DMSO-d₆) δ=9.21 (s, 1H), 8.15 (d, J=5.1 Hz, 1H), 7.96(d, J=8.3 Hz, 1H), 7.81 (br. s., 1H), 7.16-7.22 (m, 1H), 7.06 (d, J=8.3Hz, 1H), 6.88 (s, 1H), 4.54 (br. s., 2H), 4.38 (d, J=6.6 Hz, 2H), 4.13(br. s., 1H), 3.73 (br. s., 8H), 3.31-3.60 (m, 1H), 1.77 (d, J=13.7 Hz,4H), 1.65 (br. s., 1H), 1.32-1.44 (m, 2H), 1.15-1.32 (m, 2H), 1.06 (t,J=7.0 Hz, 1H). MS m/z (M+H⁺) 446.

Compounds #2 through 28 may be similarly prepared according to theprocedures as described in Example 1, above and substituting suitablyselected and/or substituted reagents, starting materials andpurification methods known to those skilled in the art.

Example 2 (In Vitro Assay): MGL Enzyme Activity Assay

All rate-based assays were performed in black 384-well polypropylene PCRmicroplates (Abgene) in a total volume of 30 μL. Substrate4-methylumbelliferyl butyrate (4MU-B, Sigma) and purified mutant MGLenzyme (mut-MGLL 11-313 L179S L186S) were diluted separately into 20 mMPIPES buffer (pH 7), containing 150 mM NaCl, and 0.001% Tween 20.Compounds of Formula (I) were pre-dispensed (50 mL) into the assay plateusing a Cartisian Hummingbird (Genomic Solutions, Ann Arbor, Mich.)prior to adding 4MU-B (25 μL of 1.2× solution, final concentration of 10μM) followed by enzyme (5 μL of a 6× solution, final concentration of 5nM) to initiate the reaction. Final compound concentrations ranged from17 to 0.0003 μM. The fluorescence change due to 4MU-B cleavage wasmonitored with excitation and emission wavelengths of 335 and 440 nm,respectively, and a bandwidth of 10 nm (Safire², Tecan) at 37° C. for 5min.

The IC₅₀ values for compounds of Formula (I) were determined using Excelfrom a fit of the equation to the concentration-response-plot of thefractional activity as a function of inhibitor concentration.

Example 3 (In Vitro Assay): MGL ThermoFluor® Assay

The ThermoFluor (TF) assay is a 384-well plate-based binding assay thatmeasures thermal stability of proteins (Pantoliano, M. W., Petrella, E.C., Kwasnoski, J. D., Lobanov, V. S., Myslik, J., Graf, E., Carver, T.,Asel, E., Springer, B. A., Lane, P., and Salemme, F. R. J Biomol Screen2001, 6, 429-40; Matulis, D., Kranz, J. K., Salemme, F. R., and Todd, M.J. Biochemistry 2005, 44, 5258-66). The experiments were carried outusing instruments available from Johnson & Johnson PharmaceuticalResearch & Development, LLC. TF dye used in all experiments was 1,8-ANS(Invitrogen: A-47). Final TF assay conditions used for MGL studies were0.07 mg/ml of purified mutant MGL (mut-MGLL 11-313 L179S L186S), 100 μMANS, 200 mM NaCl, 0.001% Tween-20 in 50 mM PIPES (pH=7.0).

Screening compound plates contained 100% DMSO compound solutions at asingle concentration. For follow-up concentration-response studies,compounds were arranged in a pre-dispensed plate (Greiner Bio-one:781280), wherein compounds were serially diluted in 100% DMSO across 11columns within a series. Columns 12 and 24 were used as DMSO referenceand contained no compound. For both single and multiple compoundconcentration-response experiments, the compound aliquots (50 mL) wererobotically pre-dispensed directly into black 384-well polypropylene PCRmicroplates (Abgene: TF-0384/k) using the Cartesian Hummingbird liquidhandler (Genomic Solutions, Ann Arbor, Mich.). Following compounddispense, protein and dye solutions were added to achieve the finalassay volume of 3 μL. The assay solutions were overlayed with 1 μL ofsilicone oil (Fluka, type DC 200: 85411) to prevent evaporation.

Bar-coded assay plates were robotically loaded onto a thermostaticallycontrolled PCR-type thermal block and then heated from 40 to 90° C.degrees at a ramp-rate of 1° C./min for all experiments. Fluorescencewas measured by continuous illumination with UV light (Hamamatsu LC6)supplied via fiber optics and filtered through a band-pass filter(380-400 nm; >60D cutoff). Fluorescence emission of the entire 384-wellplate was detected by measuring light intensity using a CCD camera(Sensys, Roper Scientific) filtered to detect 500±25 nm, resulting insimultaneous and independent readings of all 384 wells. A single imagewith 20-sec exposure time was collected at each temperature, and the sumof the pixel intensity in a given area of the assay plate was recordedversus temperature and fit to standard equations to yield the T_(m).(Pantoliano, M. W., Petrella, E. C., Kwasnoski, J. D., Lobanov, V. S.,Myslik, J., Graf, E., Carver, T., Asel, E., Springer, B. A., Lane, P.,and Salemme, F. R., J Biomol Screen 2001, 6, 429-40).

Example 4 2-AG Accumulation Assay

HeLa cells were homogenated with a Polytron in 10 ml (about 400 millioncells) HEPES buffer (HEPES 20 mM, pH 7.4, NaCl 125 mM, EDTA 1 mM, KCl 5mM, Glucose 20 mM). The homogenate from 20 million cells (0.5 ml) wasincubated with MGL inhibitor for 15 min to block MGL activity and thenthe HEPES buffer solution was incubated with calcium (10 mM) for 20 min.The total reaction volume was 5 ml. The reactions were stopped by 6 mLorganic solvent extraction (2:1 chloroform/methanol). Methoxyarachidonyl fluorophosphonate (MAFP) was used as positive control. Inthe absence of MAFP the 2-AG levels are about 3.4 pmol/sample. In thepresence of 100 nM MAFP 2-AG levels increase to 174 pmol/sample.Accumulated 2-AG in the organic phase was measured by a HPLC/MS method,according to the following equation: % MAFP=(Compound 2-AG/MAFP2-AG)×100.

Representative compounds of formula (I) were tested according to theprocedure as described in Example 2, 3 and 4 above, with results aslisted in Table 4.

TABLE 4 Example 4 Example 4 Cmpd Example 2 Example 3 % MAFP @ % MAFP @No. IC₅₀ (μM) K_(d) (μM) 1 μM 10 μM 1 0.031 0.001 2 0.050 0.130 39.787.6 3 0.055 0.091 45.7 82.9 4 0.060 0.002 5 0.077 0.008 82.9 6 0.1000.048 30.6 68.8 7 0.186 0.083 79.5 8 0.220 0.330 72.9 9 0.230 0.040 67.810 0.330 0.020 160.1 11 0.350 0.010 160.1 12 0.360 5.000 142.0 13 0.4300.030 93.5 14 0.440 5.000 53.7 15 0.470 1.850 57.6 16 0.810 4.550 61.117 0.880 4.000 25.9 18 0.920 0.050 134.6 19 1.073 0.172 19.9 47.3 201.340 5.560 86.9 21 1.420 6.670 29.2 22 1.670 5.560 50.1 23 1.890 2.50084.5 24 1.980 5.000 58.8 25 3.810 6.670 65.8 26 5.460 11.110 37.0 279.441 28.569 76.3 28 0.090 77.0

Example 5 Oral Formulation—Prophetic Example

As a specific embodiment of an oral composition, 100 mg of the compound#1, prepared as in Example 1 is formulated with sufficient finelydivided lactose to provide a total amount of 580 to 590 mg to fill asize O hard gel capsule.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1.-15. (canceled)
 16. A method of treating or ameliorating inflammatorypain, wherein the inflammatory pain is due to a disease, condition,syndrome, disorder, or a pain state selected from the group consistingof inflammatory bowel disease, visceral pain, migraine, post operativepain, osteoarthritis, rheumatoid arthritis, back pain, lower back pain,joint pain, abdominal pain, chest pain, labor, musculoskeletal diseases,skin diseases, toothache, pyresis, burn, sunburn, snake bite, venomoussnake bite, spider bite, insect sting, neurogenic bladder, interstitialcystitis, urinary tract infection, rhinitis, contactdermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis,enteritis, irritable bowel syndrome, cholecystitis, pancreatitis,postmastectomy pain syndrome, menstrual pain, endometriosis, pain due tophysical trauma, headache, sinus headache, tension headache, andarachnoiditis, the method comprising administering to a subject in needthereof, a therapeutically effective amount of a compound of formula (I)

selected from the group consisting of a compound wherein W is N, R¹ isH,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenoxymethyl, and R³ is2,2-dimethylpropyl; a compound wherein W is N, R¹ is H,

is

X—Y—Z is —O—C(R²)═N—, and R² is 3-fluorophenyl; a compound wherein W isN, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is 4-methylphenyl, and R³ is isobutyl; acompound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenylmethyl, and R³ is isobutyl; acompound wherein W is N, R¹ is H,

is

X—Y—Z is —O—C(R²)═N—, and R² is 4-fluorophenyl; a compound wherein W isN, R¹ is H,

is

X—Y—Z is —O—C(R²)═N—, and R² is 4-methoxyphenyl; a compound wherein W isN, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is isobutyl, and R³ is isobutyl; acompound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenoxymethyl, and R³ is isobutyl; acompound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenyl, and R³ is 2,2-dimethylpropyl; acompound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenoxymethyl, and R³ iscyclohexylmethyl; a compound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is cyclopentylmethyl, and R³ is methyl; acompound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenyl, and R³ is isobutyl; a compoundwherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is cyclohexylmethyl, and R³ is hydrogen; acompound wherein W is N, R¹ is H,

is

X—Y—Z is —O—C(R²)═N—, and R² is 2-methoxyphenylmethyl; a compoundwherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is n-propyl, and R³ is methyl; a compoundwherein W is CH, R¹ is 2-methoxy,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenoxymethyl, and R³ is isobutyl; acompound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenylmethyl, and R³ iscyclohexylmethyl; a compound wherein W is N, R¹ is H,

is

X—Y—Z is —O—C(R²)═N—, and R² is t-butyl; a compound wherein W is N, R¹is H,

is

X—Y—Z is —O—C(R²)═N—, and R² is 3-methoxyphenyl; a compound wherein W isCH, R¹ is 2-methoxy,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenylmethyl, and R³ is isobutyl; acompound wherein W is CH, R¹ is 2-methoxy,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenoxymethyl, and R³ is2,2-dimethylpropyl; a compound wherein W is CH, R¹ is 2-methoxy,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenylmethyl, and R³ iscyclohexylmethyl; a compound wherein W is CH, R¹ is 2-methoxy,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenyl, and R³ is 2,2-dimethylpropyl; acompound wherein W is CH, R¹ is 4-fluoro,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenyl, and R³ is 2,2-dimethylpropyl; acompound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is t-butyl, and R³ is 2,2-dimethylpropyl;a compound wherein W is N, R¹ is H,

is

X—Y—Z is —NH—C(R²)—C(R³)—, R² is 4-methylphenyl and R³ ismethoxy-methyl-carbonyl; a compound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³), R² is n-propyl and R³ is cyclohexylmethyl; andenantiomers, diastereomers and pharmaceutically acceptable saltsthereof.
 17. A method as in claim 16, wherein the compound of formula(I) is selected form the group consisting of a compound wherein W is N,R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenoxymethyl, and R³ is2,2-dimethylpropyl; a compound wherein W is N, R¹ is H,

is

X—Y—Z is —O—C(R²)═N—, and R² is 3-fluorophenyl; a compound wherein W isN, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is 4-methylphenyl, and R³ is isobutyl; acompound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenylmethyl, and R³ is isobutyl; acompound wherein W is N, R¹ is H,

is

X—Y—Z is —O—C(R²)═N—, and R² is 4-fluorophenyl; a compound wherein W isN, R¹ is H,

is

X—Y—Z is —O—C(R²)═N—, and R² is 4-methoxyphenyl; a compound wherein W isN, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is isobutyl, and R³ is isobutyl; acompound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenoxymethyl, and R³ is isobutyl; acompound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenyl, and R³ is 2,2-dimethylpropyl; acompound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenoxymethyl, and R³ iscyclohexylmethyl; a compound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is cyclopentylmethyl, and R³ is methyl; acompound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenyl, and R³ is isobutyl; a compoundwherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is cyclohexylmethyl, and R³ is hydrogen; acompound wherein W is N, R¹ is H,

is

X—Y—Z is —O—C(R²)═N—, and R² is 2-methoxyphenylmethyl; a compoundwherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is n-propyl, and R³ is methyl; a compoundwherein W is CH, R¹ is 2-methoxy,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenoxymethyl, and R³ is isobutyl; acompound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenylmethyl, and R³ iscyclohexylmethyl; and enantiomers, diastereomers and pharmaceuticallyacceptable salts thereof.
 18. A method as in claim 16, wherein thecompound of formula (I) is selected form the group consisting of acompound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenoxymethyl, and R³ is2,2-dimethylpropyl; a compound wherein W is N, R¹ is H,

is

X—Y—Z is —O—C(R²)═N—, and R² is 3-fluorophenyl; a compound wherein W isN, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is 4-methylphenyl, and R³ is isobutyl; acompound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenylmethyl, and R³ is isobutyl; acompound wherein W is N, R¹ is H,

is

X—Y—Z is —O—C(R²)═N—, and R² is 4-fluorophenyl; a compound wherein W isN, R¹ is H,

is

X—Y—Z is —O—C(R²)═N—, and R² is 4-methoxyphenyl; a compound wherein W isN, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenoxymethyl, and R³ is isobutyl; acompound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenyl, and R³ is 2,2-dimethylpropyl; acompound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenoxymethyl, and R³ iscyclohexylmethyl; a compound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenyl, and R³ is isobutyl; a compoundwherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenylmethyl, and R³ iscyclohexylmethyl; a compound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³), R² is n-propyl and R³ is cyclohexylmethyl; andenantiomers, diastereomers and pharmaceutically acceptable saltsthereof.
 19. A method as in claim 16, wherein the compound of formula(I) is selected form the group consisting of a compound wherein W is N,R¹ is H,

is

X—Y—Z is —O—C(R²)═N—, and R² is 3-fluorophenyl; a compound wherein W isN, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenylmethyl, and R³ is isobutyl; acompound wherein W is N, R¹ is H,

is

X—Y—Z is —O—C(R²)═N—, and R² is 4-methoxyphenyl; a compound wherein W isN, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenyl, and R³ is 2,2-dimethylpropyl; acompound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenoxymethyl, and R³ iscyclohexylmethyl; a compound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is cyclopentylmethyl, and R³ is methyl; acompound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenyl, and R³ is isobutyl; a compoundwherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenylmethyl, and R³ iscyclohexylmethyl; a compound wherein W is N, R¹ is H,

is

X—Y—Z is —O—C(R²)═N—, and R² is 3-methoxyphenyl; a compound wherein W isCH, R¹ is 2-methoxy,

is

X—Y—Z is —CH—C(R²)—N(R³)—, R² is phenylmethyl, and R³ iscyclohexylmethyl; a compound wherein W is N, R¹ is H,

is

X—Y—Z is —NH—C(R²)—C(R³)—, R² is 4-methylphenyl and R³ ismethoxy-methyl-carbonyl; a compound wherein W is N, R¹ is H,

is

X—Y—Z is —CH—C(R²)—N(R³), R² is n-propyl and R³ is cyclohexylmethyl; andenantiomers, diastereomers and pharmaceutically acceptable saltsthereof.
 20. A method as in claim 16, wherein the compound of formula(I) is selected form the group consisting of a compound wherein W is N,R¹ is H,

is

X—Y—Z is —O—C(R²)═N—, and R² is 3-fluorophenyl; a compound wherein W isN, R¹ is H,

is

X—Y—Z is —O—C(R²)═N—, and R² is 4-fluorophenyl; a compound wherein W isN, R¹ is H,

is

X—Y—Z is —O—C(R²)═N—, and R² is t-butyl; and enantiomers, diastereomersand pharmaceutically acceptable salts thereof.